DESCRIPTION: (provided by the applicant): Infection with Trypanosoma cruzi often leads to a chronic debilitating and sometimes-fatal disease. Disease is the result of the persistence of parasites in specific tissue sites and the severity of disease is determined by the efficiency of the immune response to persistent infection. A critical component of immune control of T. cruzi is CD8+ T cells which are capable of cytokine secretion and cytolytic activity targeted at T. cruzi -infected host cells. The goals of this project are to understand the evolution of the CD8+ T cell response during the course of T. cruzi infection and the impact of the development of that response on the course of infection and disease. The activation, expansion and contraction, generation of effector function and memory cells throughout the course of infection will be assayed using a combination of phenotypic markers, intracellular cytokine staining, MHC class I tetramers and TCR transgenic T cells. The relationship between the CD8+ T cell response and infection and disease will be addressed by also measuring parasite tissue load using quantitative real time PCR. The mechanism of parasite persistence in muscle despite an active immune response will be investigated with specific attention on the role of TGF-beta in modulating effector function in these tissues. Lastly, the CD8+ T cell response will be altered in infected mice by vaccination or the transfer of parasite-specific memory CD8+ T cells and the effect of this alteration on the course of infection and disease will be determined. Completion of these studies will provide a comprehensive view of the development of CD8+ T cell responses in this complex infection and will provide leads as to how to modulate this response for more effective control of infection and disease. These studies will also provide definitive information on a number of issues, which have plagued research in T. cruzi infection, including the extent of polyclonal activation in the infection and the degree to which an over-aggressive immune response contributes to disease.